Controlled delivery of active agents

ABSTRACT

Controlled release of active agents from sustained release push delivery devices having high drug loading are described wherein residual drug content in the device is minimized by the utilization of a flow-promoting layer between a semi-permeable wall and drug layer comprising the device.

CONTROLLED DELIVERY OF ACTIVE AGENTS

This application a continuation of application Ser. No. 09/430,837 filedNov. 1, 1999, now U.S. Pat. No. 6,368,626 which claims the benefit ofprovisional application Ser. No. 60/106,739, filed Nov. 2, 1998, whichis incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to the controlled delivery of pharmaceuticalagents and dosage forms therefor. In particular, the invention isdirected to improved methods, dosage forms and devices for thesubstantially complete release of active agents from dosage forms havingan expandable push layer and a drug layer that is to be dispensed to theenvironment of use.

BACKGROUND OF THE INVENTION

Certain drugs may have to be delivered in large doses, sometimes severaltimes per day, to achieve a desired therapeutic effect. While largedaily doses of drug may be administered by multiple dosing throughoutthe day, multiple dosing regimens are often not preferred because ofpatient compliance problems, potential side effects and the dangers ofoverdosing. Accordingly, there has been a movement to once-a-day ortwice-a-day dosing regimens when possible, even when there is a need forlarge doses of drug to be delivered over a prolonged period, for example12 hours to 24 hours, as the case may be.

High ranges of daily dosing may require drug loading in drugcompositions of the dosage forms to be as much as 20% to 90% or more ofthe overall weight of the composition. Such loading requirements maypresent problems in formulating compositions and fabricating dosageforms that are suitable for oral administration and can be swallowedwithout undue difficulty. High drug loading may present even greaterproblems when formulating dosage forms that are to be administered alimited number of times per day, such as for once-a-day dosing, becauseof the large unit dosage form required.

Various devices and methods have been described having intended utilitywith respect to applications with high drug loading. For example, U.S.Pat. Nos. 4,892,778 and 4,940,465, which are incorporated herein byreference, describe dispensers for delivering a beneficial agent to anenvironment of use that include a semipermeable wall defining acompartment containing a layer of expandable material that pushes a druglayer out of the compartment formed by the wall. The exit orifice in thedevice is substantially the same diameter as the inner diameter of thecompartment formed by the wall.

U.S. Pat. No. 4,915,949, which is incorporated herein by reference,describes a dispenser for delivering a beneficial agent to anenvironment of use that includes a semipermeable wall containing a layerof expandable material that pushes a drug layer out of the compartmentformed by the wall. The drug layer contains discrete tiny pillsdispersed in a carrier. The exit orifice in the device is substantiallythe same diameter as the inner diameter of the compartment formed by thewall.

U.S. Pat. No. 5,126,142, which is incorporated herein by reference,describes a device for delivering an ionophore to livestock thatincludes a semipermeable housing in which a composition containing theionophore and a carrier and an expandable hydrophilic layer is located,along with an additional element that imparts sufficient density to thedevice to retain it in the rumen-reticular sac of a ruminant animal. Theionophore and carrier are present in a dry state during storage and thecomposition changes to a dispensable, fluid-like state when it is incontact with the fluid environment of use. A number of different exitarrangements are described, including a plurality of holes in the end ofthe device and a single exit of varying diameter to control the amountof drug released per unit time due to diffusion and osmotic pumping.

Other devices in which the drug composition is delivered as a slurry,suspension or solution from a small exit orifice by the action of anexpandable layer are described in U.S. Pat. Nos. 5,660,861, 5,633,011;5,190,765; 5,252,338; 5,620,705; 4,931,285; 5,006,346; 5,024,842; and5,160,743. Typical devices include an expandable push layer and a druglayer surrounded by a semipermeable membrane. In certain instances, thedrug layer is provided with a subcoat to protect the drug composition inthose portions of the gastrointestinal tract having acidic pH, to delayrelease of the drug composition to the environment of use or to form anannealed coating in conjunction with the semipermeable membrane.However, such devices generally are not well suited as dosage forms forhigh drug loading due to size requirements necessary to accommodatelarge amounts of drug in a slurry, suspension or solution, and the needto have an oral dosage form conveniently sized so that it can beswallowed.

Another dosage form is disclosed in U.S. Pat. 5,536,507 that describes athree component pharmaceutical formulation that utilizes, inter alia, apH sensitive polymer, optionally including an osmotic agent, that willswell in the higher pH regions of the lower portion of the smallintestine and the large intestine to release drug in those environments.Additional components of the dosage form include a delayed releasecoating and an enteric coating to provide a dosage form that releasesvery little, if any, of the drug in the stomach, a relatively minimalamount in the small intestine and reportedly about 85% or more in thelarge intestine. Such a dosage form provides a widely varyingtime-release of drug after administration that may not begin for 1-3hours until the dosage form has passed from the stomach and anadditional 3 hours or more for the dosage form to pass into the largeintestine.

U.S. Pat. 5,169,638 describes a buoyant controlled releasepharmaceutical powder formulation to be filled into capsules that uses apH dependent polymer formed from alginic acid and hydroxypropylmethylcellulose to release pharmaceuticals at a controlled rate. It appearsfrom the disclosure that the capsule formulation was intended to mimicthe characteristics of a tableted formulation.

In the case of high drug loading, it is often preferable that a largeorifice, from about 50%-100% of the inner diameter of the drugcompartment, is provided in the dispensing device so that the drug layercan be dispensed in a non-fluid state. When exposed to the environmentof use, drug is released from the drug layer by erosion and diffusion. Acommon problem associated with the release of drug from prior art dosageforms in which the drug layer is dispensed from the delivery device in adry state is that a residual amount of drug often is left in the deviceand not released to the subject. Upwards of 20-30% of the drug loadingof the composition may remain in the device without being released. Inorder to compensate for that deficiency, prior art methods haveroutinely provided for overloading of drug such that the required amountis delivered notwithstanding that a substantial amount remainsunreleased in the delivery device. Loading an excess amount of drugfurther exacerbates the problems of dosage forms that are large anddifficult to swallow. Also, the added cost may be significant for activeagents having a high material or manufacturing cost. Consequently, thereis a need for improved delivery devices having an expandable push layerand a drug layer suitable for use with high drug loading that releasesubstantially all of the drug from the device to the environment of use.

SUMMARY OF THE INVENTION

In one aspect, the invention comprises a delivery device for an activeagent comprising a wall defining a cavity, the wall having an exitorifice formed or formable therein and at least a portion of the wallbeing semipermeable; an expandable layer located within the cavityremote from the exit orifice and in fluid communication with thesemipermeable portion of the wall; a drug layer located within thecavity adjacent the exit orifice and in direct or indirect contactingrelationship with the expandable layer; and a flow-promoting layerinterposed between the inner surface of the wall and at least theexternal surface of the drug layer located within the cavity.

In another aspect, the invention comprises an article of manufacturecomprising a compressed drug composition overcoated with aflow-promoting layer. The compressed drug composition may be formed as alayer in direct or indirect contact with an expandable layer to form abilayer core that is overcoated with a flow-promoting layer.

In yet another aspect, the invention comprises a method of facilitatingthe release of a drug from a device comprising a compressed drugcomposition, a semipermeable wall and a push-layer, the methodcomprising interposing a flow-promoting layer between the semi-permeablewall and the compressed drug composition.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A and 1B illustrate one embodiment of a dosage form of thisinvention, FIG. 1A illustrating the dosage form prior to administrationto a subject and FIG. 1B illustrating the dosage form at a period oftime after administration to a subject;

FIG. 2 illustrates a release profile (release rate as a function oftime) of the active agent nefazodone hydrochloride from a representativedosage form having the general characteristics illustrated in FIG. 1,formed with an orifice of 190 mils and containing 400 mg of nefazodonehydrochloride;

FIG. 3 illustrates a release profile (release rate as a function oftime) of the active agent nefazodone hydrochloride from a representativedosage form having the general characteristics of FIG. 1, formed with anorifice of 117 mils and containing 100 mg of nefazodone hydrochloride;

FIG. 4 illustrates the cumulative release of nefazodone hydrochlorideover time for a number of representative dosage forms containingpolyethylene oxide-based nefazodone hydrochloride granulations, with 100mg loading of nefazodone hydrochloride and an orifice of 117 mils;

FIG. 5 illustrates the release profile (release rate as a function oftime) of the active agent nefazodone hydrochloride for representativedosage forms prepared in accordance with the procedure of Example 3;

FIG. 6 illustrates the cumulative release of nefazodone hydrochlorideover time for representative dosage forms prepared in accordance withthe procedure of Example 3;

FIG. 7 illustrates the release profile (release rate as a function oftime) of the active agent nefazodone hydrochloride for representativedosage forms prepared in accordance with the procedure of Example 4;

FIG. 8 illustrates the cumulative release of nefazodone hydrochlorideover time for representative dosage forms prepared in accordance withthe procedure of Example 4;

FIG. 9 illustrates the release profile (release rate as a function oftime) of the active agent nefazodone hydrochloride for representativedosage forms prepared in accordance with the procedure of Example 5;

FIG. 10 illustrates the cumulative release of nefazodone hydrochlorideover time for representative dosage forms prepared in accordance withthe procedure of Example 5;

FIG. 11 illustrates the release profile (release rate as a function oftime) of the active agent nefazodone hydrochloride for representativedosage forms prepared in accordance with the procedure of Example 6;

FIG. 12 illustrates the cumulative release of nefazodone hydrochlorideover time for representative dosage forms prepared in accordance withthe procedure of Example 6; and

FIGS. 13A-13D provide a comparison of the release rate profile andcumulative release as a function of time for coated and uncoated dosageforms containing 400 mg of nefazodone hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is best understood by reference to the followingdefinitions, the drawings and exemplary disclosure provided herein.

Definitions By “active agent”, “drug”, or “compound”, which are usedinterchangeably herein, is meant an agent, drug, compound, compositionof matter or mixture thereof which provides some physiological,psychological, biological, or pharmacological, and often beneficial,effect when administered to a subject.

By “uniform rate of release” or “uniform release rate” is meant a rateof release of the active agent from a dosage form that does not varypositively or negatively by more than 30% from the mean rate of releaseof the active agent over a prolonged period of time, as determined in aUSP Type 7 Interval Release Apparatus. Preferred uniform rates ofrelease will vary by not more than 25% (positively or negatively) fromthe mean rate of release determined over a prolonged period of time.

By “prolonged period of time” or “prolonged period” is meant acontinuous period of time of 4 hours or more, more typically 6 hours ormore.

By “dosage form” is meant a pharmaceutical composition or devicecomprising an active pharmaceutical agent, the composition or deviceoptionally containing inactive ingredients, such aspharmaceutically-acceptable carriers, excipients, suspension agents,surfactants, disintegrants, binders, diluents, lubricants, stabilizers,antioxidants, osmotic agents, colorants, plasticizers, and the like,that are used to manufacture and deliver active pharmaceutical agents.

By “pharmaceutically-acceptable acid addition salt” or“pharmaceutically-acceptable salt”, which are used interchangeablyherein, are meant those salts in which the anion does not contributesignificantly to the toxicity or pharmacological activity of the salt,and, as such, they are the pharmacological equivalents of the bases ofthe compounds to which they refer. Examples of pharmaceuticallyacceptable acids that are useful for the purposes of salt formationinclude but are not limited to hydrochloric, hydrobromic, hydroiodic,citric, acetic, benzoic, mandelic, phosphoric, nitric, mucic,isethionic, palmitic, and others.

By “sustained release” is meant continuous release of active agent to anenvironment over a prolonged period.

By “steady state” is meant the condition in which the amount of drugpresent in the blood plasma of a subject does not vary significantlyover a prolonged period of time.

By “C” is meant the concentration of drug in the blood plasma of asubject, generally expressed as mass per unit volume, typicallynanograms per milliliter.

By “C_(max)” is meant the maximum concentration of drug in the bloodplasma of a subject, generally expressed as mass per unit volume,typically nanograms per milliliter, within a specified time intervalafter administration of the drug to a subject.

By “C_(min)” is meant the minimum concentration of drug in the bloodplasma of a subject, generally expressed as mass per unit volume,typically nanograms per milliliter, within a specified time intervalafter administration of the drug to a subject.

By “release rate assay” is meant a standardized assay for thedetermination of a compound using a USP Type 7 interval releaseapparatus substantially in accordance with the description of Example 2.It is understood that reagents of equivalent grade may be substituted inthe assay in accordance with generally-accepted procedures.

By “dry state” or “substantially dry state” is meant that thecomposition forming the drug layer of the dosage form is expelled fromthe dosage form in a plug-like state, the composition being sufficientlydry or so highly viscous that it does not readily flow as a liquidstream from the dosage form under the pressure exerted by the pushlayer.

One of the most suitable devices for the controlled release of drugsthat require high loading in the dosage form to deliver an amount ofdrug having the desired therapeutic effect is that having asemipermeable wall defining a compartment, an expandable push layer anda drug layer in the compartment, and an exit orifice formed in thedosage form to permit the drug layer to be dispensed in a substantiallydry state to the environment of use. When manufacturing such dosageforms, a common practice is to fabricate a compressed tablet comprisingthe drug layer and the push layer. Typically, the push layercomposition, conveniently in granulated or powdered form, is compressedin a die cavity of a vertical tableting press. Then the drug layercomposition, also conveniently in granular or powdered form, is placedin the die cavity above the push layer and compressed as well to form abilayer tablet. Although the surface of the die cavity is quite smooth,the formed bilayer tablet may still be formed with surfaceirregularities. This is more of a problem with the drug layer,particularly when high drug loading is involved such that the amounts oflubricant, carrier and binder used may be limited due to sizeconstraints, than with the push layer.

In many applications the irregularities in the drug layer as describedabove may be of little importance. However, when the drug layer is to bedispensed in a dry state from the compartment formed by thesemipermeable wall, the outer surface of the drug layer is pushed alongthe inner surface of the semipermeable wall. Resistance to movement ofthe drug layer will be present because of the frictional force existingbetween the two surfaces. The degree of resistance will increase as thenumber and degree of irregularities in the external surface of the druglayer and the inner surface of the semipermeable wall increase.Furthermore, because it is practical to form the semipermeable wall bycoating the bilayer drug core, the inner surface of the semipermeablewall will initially conform to the irregularities present in theexternal surface of the drug layer. Then when the drug layer is forcedto move past the semipermeable wall, the irregularities on the externalsurface of the drug layer must be forced over the irregularities on theinner surface of the semipermeable wall. This creates friction andresistance to movement of the respective layers. While each of thesurfaces is substantially a solid, it is convenient to view the relativemovement of (i) the drug layer or drug layer/push layer composite and(ii) the semipermeable outer wall as a “flow” of the drug layer from thedevice as the push layer expands. Thus, the inner layer or subcoat ischaracterized as a “flow-promoting” layer. In effect, the flow-promotinglayer is a layer of material interposed between the external surface ofthe drug layer and the internal surface of the semipermeable wall thatreduces friction between the two and facilitates the relative movementbetween them as fluid passes through the semipermeable wall and isimbibed by the expandable layer.

In systems without the flow promoting layer, the resistance between thedrug layer and the outer semipermeable wall may create several problems.One is that the magnitude of the force resisting transport of the druglayer may be a function of the relative positions of the drug layer andthe outer wall at any period in time. Variations in the magnitude of theresisting force may cause variations in the rate at which the drug layeris expressed to the environment of use. This would then cause variationsin the release of drug from the dosage form and potentially variationsin drug plasma levels of drug in the subject over time. As can be seenfrom the release profiles of the dosage forms described herein, with thepractice of the invention active agent is uniformly released from thedosage forms over a prolonged period of time. Such uniform release mayprovide significant pharmacological advantages in the delivery of activeagents.

Secondly, without the flow promoting layer being present, a portion ofthe drug layer tends to “stick” to the inner surface of the outer walland remain in the dosage form as the rest of the drug layer is expressedto the environment of use by the expanding layer. This residual amountof undispensed drug may be large; residual amounts of more than 20% to30% of the initial drug layer loading have been observed underconditions of high drug loading.

The invention provides a dosage form, article of manufacture and methodfor the substantially complete release of a drug from the dosage form,particularly from dosage forms that may require high drug loading inorder to have the desired pharmacological effect. Dosage forms preparedin accordance with this invention may result in a depleted dosage formretaining 20% or less by weight, preferably 10% or less by weight, andmost preferably 5% or less by weight of the initial amount of drugloaded in the dosage form when tested in a standard release rate assay.

High ranges of drug dosing, e.g. 100 to 2,000 mg of drug per unit dose,may require drug loading in the compositions to be administered of 20%to 90% or more of the overall weight of the composition. Such loadingrequirements may present problems in formulating compositions andfabricating devices that are suitable for oral administration and can beswallowed without undue difficulty. Loading requirements provide evengreater problems when formulating dosage forms that are to beadministered a limited number of times per day, such as for once-a-daydosing. Size problems are exacerbated when not all of the drugcomposition is released from the delivery device, since overloading ofthe drug, i.e. providing a quantity in the delivery device greater thanthat which will be released to the subject to provide the desiredpharmacological effect, is necessary to ensure that an appropriatequantity of drug is made available to the subject.

Dosage forms of this invention release effective amounts of active agentto the patient over a prolonged period of time and often provide theopportunity for less frequent dosing, including once-a-day dosing, thanpreviously required for immediate release compositions. The dosage formsof this invention comprise a composition containing an active agent,wherein the composition is externally coated with a flow-promotinglayer.

Active agents include, inter allia, foods, food supplements, nutrients,drugs, antacids, vitamins, microorganism attenuators and other agentsthat benefit the environment of use. Active agents include anyphysiologically or pharmacologically active substance that produces alocalized or systemic effect or effects in animals, including warmblooded mammals, humans and primates; domestic household or farm animalssuch as cats, dogs, sheep, goats, cattle, horses and pigs; laboratoryanimals such as mice, rats and guinea pigs; zoo and wild animals; andthe like. Active agents that can be delivered include inorganic andorganic compounds, including, without limitation, active agents whichact on the peripheral nerves, adrenergic receptors, cholinergicreceptors, the skeletal muscles, the cardiovascular system, smoothmuscles, the blood circulatory system, synoptic sites, neuroeffectorjunctional sites, endocrine and hormone systems, the immunologicalsystem, the reproductive system, the skeletal system, autacoid systems,the alimentary and excretory systems, the histamine system and thecentral nervous system.

Suitable active agents may be selected from, for example, proteins,enzymes, enzyme inhibitors, hormones, polynucleotides, nucleoproteins,polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids,hypnotics and sedatives, psychic energizers, tranquilizers,anticonvulsants, antidepressants, muscle relaxants, antiparkinsonagents, analgesics, anti-inflammatories, antihystamines, localanesthetics, muscle contractants, antimicrobials, antimalarials,antivirals, antibiotics, antiobesity agents, hormonal agents includingcontraceptives, sympathomimetics, polypeptides and proteins capable ofeliciting physiological effects, diuretics, lipid regulating agents,antiandrogenic agents, antiparasitics, neoplastics, antineoplastics,antihyperglycemics, hypoglycemics, nutritional agents and supplements,growth supplements, fats, ophthalmics, antienteritis agents,electrolytes and diagnostic agents.

Examples of particular active agents useful in this invention includeprochlorperazine edisylate, ferrous sulfate, albuterol, aminocaproicacid, mecamylamine hydrochloride, procainamide hydrochloride,amphetamine sulfate, methamphetamine hydrochloride, benzphetaminehydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride,bethanechol chloride, methacholine chloride, pilocarpine hydrochloride,atropine sulfate, scopolamine bromide, isopropamide iodide,tridihexethyl chloride, phenformin hydrochloride, methylphenidatehydrochloride, theophylline cholinate, cephalexin hydrochloride,diphenidol, meclizine hydrochloride, prochlorperazine maleate,phenoxybenzamine, triethylperazine maleate, anisindione, diphenadioneerythrityl tetranitrate, digoxin, isoflurophate, acetazolamide,nifedipine, methazolamide, bendroflumethiazide, chlorpropamide,glipizide, glyburide, gliclazide, tobutamide, chlorproamide, tolazamide,acetohexamide, metformin, troglitazone, orlistat, bupropion, nefazodone,tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminumaspirin, methotrexate, acetyl sulfisoxazole, hydrocortisone,hydrocorticosterone acetate, cortisone acetate, dexamethasone and itsderivatives such as betamethasone, triamcinolone, methyltestosterone,17-β-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether,prednisolone, 17-β-hydroxyprogesterone acetate, 19-nor-progesterone,norgestrel, norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, terfandine, fexofenadine, aspirin,acetaminophen, indomethacin, naproxen, fenoprofen, sulindac, indoprofen,nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol,alprenolol, cimetidine, clonidine, imipramine, levodopa, selegiline,chlorpromazine, methyldopa, dihydroxyphenylalanine, calcium gluconate,ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac,ferrous lactate, vincamine, phenoxybenzamine, diltiazem, milrinone,captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenbufen, fluprofen, tolmetin, alclofenac, mefenamic,flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinopril, enalapril, captopril, ramipril, enalaprilat,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptyline, and imipramine, andpharmaceutical salts of these active agents. Further examples areproteins and peptides which include, but are not limited to, insulin,colchicine, glucagon, thyroid stimulating hormone, parathyroid andpituitary hormones, calcitonin, renin, prolactin, corticotrophin,thyrotropic hormone, follicle stimulating hormone, chorionicgonadotropin, gonadotropin releasing hormone, bovine somatotropin,porcine somatropin, oxytocin, vasopressin, desmopressin, prolactin,somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH,interferons, interleukins, growth hormones such as human growth hormone,bovine growth hormone and porcine growth hormone, fertility inhibitorssuch as the prostaglandins, fertility promoters, growth factors, andhuman pancreas hormone releasing factor.

Active agents in the field of antidepressants may be selected from thegroup consisting of tertiary amine tricyclics such as, for example,amitriptyline, clomipramine, doxepin, imipramine, (+)-trimipramine;secondary amine tricyclics such as, for example, amozapine, desipramine,maprotiline, nortiriptyline, protryptilyline; serotonin re-uptakeinhibitors such as, for example, fluoexetine, fluvoxamine, paroxetine,sertraline, venlafazine; and atypical antidepressants such asbrupropion, nefazodone, trazodone, phenelzine, tranylcypromirne,selegiline, and pharmaceutically acceptable salts thereof. The dosageform typically may include a carrier, e.g., hydrophilic polymer, in acomposition with the active agent.

With reference to FIG. 1A, a preferred embodiment of a dosage form 1 ofthis invention having the “push-stick” configuration is illustratedprior to its administration to a subject. The dosage form 1 comprises awall 2 defining a cavity 3. Wall 2 is provided with an exit orifice 4.Within cavity 3 and remote from the exit orifice 4 is a push layer 5. Adrug layer 6 is located within cavity 3 adjacent exit orifice 4. Inaccordance with the invention, a flow-promoting layer 7, the function ofwhich will be described and which may be formed as a secondary wall,extends between drug layer 6 and the inner surface of wall 2.

The wall 2 is formed to be permeable to the passage of an externalfluid, such as water and biological fluids, and it is substantiallyimpermeable to the passage of active agent, osmagent, osmopolymer andthe like. As such, it is semipermeable. The selectively semipermeablecompositions used for forming the wall are essentially nonerodible andthey are insoluble in biological fluids during the life of the dosageform. Wall 2 need not be semipermeable in its entirety. But at least aportion of wall 2 should be semipermeable to allow fluid to contact orcommunicate with push layer 5 such that push layer 5 imbibes fluidduring use. Specific materials for the fabrication of semipermeable wall2 are well known in the art, and representative examples of suchmaterials are described later herein.

Secondary wall 7, which functions as the flow-promoting layer, is incontacting position with the inner surface of the semipermeable wall 2and at least the external surface of the drug layer that is oppositewall 2; although the secondary wall 7 may, and preferably will, extendto, surround and contact the external surface of the push layer. Wall 7typically will surround at least that portion of the external surface ofthe drug layer that is opposite the internal surface of wall 2.Secondary wall 7 may be formed as a coating applied over the compressedcore comprising the drug layer and the push layer. The outersemipermeable wall 2 surrounds and encases the inner, secondary wall 7.Secondary wall 7 is preferably formed as a subcoat of at least thesurface of the drug layer 6, and optionally the entire external surfaceof the compacted drug layer 6 and the push layer 5. When thesemipermeable wall 2 is formed as a coat of the composite formed fromthe drug layer 6, the push layer 5 and the secondary wall 7, contact ofthe semipermeable wall 2 with the inner coat is assured.

Secondary wall 7 facilitates release of drug from the dosage forms ofthe invention. In dosage forms in which there is high drug loading,i.e., 20% or greater, but more generally 40% or greater, active agent inthe drug layer based on the overall weight of the drug layer, and nosecondary wall, it has been observed that significant residual amountsof drug may remain in the device after the period of delivery has beencompleted. In some instances, residual drug amounts of greater that 20%,and even greater than 30%, by weight of the initial drug loading in thedosage form may remain in the dosage form at the end of a twenty-fourhour period when tested in a release rate assay. A comparison of therelease of nefazodone hydrochloride from a representative dosage form ofthis invention having a flow promoting layer and a dosage form nothaving the flow promoting layer (the details of which are provided inEXAMPLE 8) is shown in FIGS. 13A-13D for a dosage form having a drugloading of 83% (400 mg of nefazodone hydrochloride). FIGS. 13A and 13Bare representative of the dosage form of the invention having a flowpromoting layer and FIGS. 13C and 13D are representative of a similardosage form without the flow promoting layer. The significant differencein the average, instantaneous release rates and the cumulative releaserates for the two dosage forms is apparent. Additionally, it is apparentthat after 24 hours there is significantly more drug remaining in thedosage form without the flow promoting layer than drug remaining in thedosage form having the flow promoting layer.

As noted above, the amount of residual drug may be advantageouslyreduced by the addition of secondary wall 7 formed as an inner coat of aflow-promoting agent, i.e., an agent that lowers the frictional forcebetween the outer, semi-permeable membrane wall 2 and the externalsurface of the drug layer 6. The secondary wall or inner coat 7 reducesthe frictional forces between the semipermeable wall 2 and the outersurface of the drug layer, thus allowing for more complete delivery ofdrug from the device. Particularly in the case of active compoundshaving a high cost, such an improvement presents substantial economicadvantages since it is not necessary to load the drug layer with anexcess of drug to insure that the minimal amount of drug required willbe delivered.

The inner subcoat 7 typically may be 0.01 to 5 mm thick, more typically0.5 to 5 mm thick, and it comprises a member selected from hydrogels,gelatin, low molecular weight polyethylene oxides, e.g., less than100,000 MW, hydroxyalkylcelluloses, e.g., hydroxyethylcellulose,hydroxypropylcellulose, hydroxyisopropylcelluose, hydroxybutylcelluloseand hydroxyphenylcellulose, and hydroxyalkyl alkylcelluloses, e.g.,hydroxypropyl methylcellulose, and mixtures thereof. Thehydroxyalkylcelluloses comprises polymers having a 9,500 to 1,250,000number-average molecular weight. For example, hydroxypropyl celluloseshaving number average molecular weights of between 80,000 to 850,000 areuseful. The flow promoting layer may be prepared from conventionalsolutions or suspensions of the aforementioned materials in aqueoussolvents or inert organic solvents. Preferred materials for the subcoator flow promoting layer include hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, povidone[poly(vinylpyrrolidone)], polyethylene glycol, and mixtures thereof.More preferred are mixtures of hydroxypropyl cellulose and povidone,prepared in organic solvents, particularly organic polar solvents suchas lower alkanols having 1-8 carbon atoms, preferably ethanol, mixturesof hydroxyethyl cellulose and hydroxypropyl methyl cellulose prepared inaqueous solution, and mixtures of hydroxyethyl cellulose andpolyethylene glycol prepared in aqueous solution. Most preferably, thesubcoat consists of a mixture of hydroxypropyl cellulose and povidoneprepared in ethanol. Conveniently, the weight of the subcoat applied tothe bilayer core may be correlated with the thickness of the subcoat andresidual drug remaining in a dosage form in a release rate assay such asdescribed herein. During manufacturing operations, the thickness of thesubcoat may be controlled by controlling the weight of the subcoat takenup in the coating operation. When the secondary wall 7 is formed as asubcoat, i.e., by coating onto the tableted bilayer composite drug layerand push layer, the subcoat can fill in surface irregularities formed onthe bilayer core by the tableting process. The resulting smooth externalsurface facilitates slippage between the coated bilayer composite andthe semipermeable wall during dispensing of the drug, resulting in alower amount of residual drug composition remaining in the device at theend of the dosing period. When wall 7 is fabricated of a gel-formingmaterial, contact with water in the environment of use facilitatesformation of a gel or gel-like inner coat having a viscosity that maypromote and enhance slippage between outer wall 2 and drug layer 6.

Representative polymers for forming wall 2 comprise semipermeablehomopolymers, semipermeable copolymers, and the like. Such materialscomprise cellulose esters, cellulose ethers and cellulose ester-ethers.The cellulosic polymers have a degree of substitution (DS) of theiranhydroglucose unit of from greater than 0 up to 3, inclusive. Degree ofsubstitution (DS) means the average number of hydroxyl groups originallypresent on the anhydroglucose unit that are replaced by a substitutinggroup or converted into another group. The anhydroglucose unit can bepartially or completely substituted with groups such as acyl, alkanoyl,alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate,alkylcarbonate, alkylsulfonate, alkysulfamate, semipermeable polymerforming groups, and the like, wherein the organic moieties contain fromone to twelve carbon atoms, and preferably from one to eight carbonatoms.

The semipermeable compositions typically include a member selected fromthe group consisting of cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di-and tri-cellulose alkanylates, mono-, di-, andtri-alkenylates, mono-, di-, and tri-aroylates, and the like. Exemplarypolymers include cellulose acetate having a DS of 1.8 to 2.3 and anacetyl content of 32 to 39.9%; cellulose diacetate having a DS of 1 to 2and an acetyl content of 21 to 35%; cellulose triacetate having a DS of2 to 3 and an acetyl content of 34 to 44.8%; and the like. More specificcellulosic polymers include cellulose propionate having a DS of 1.8 anda propionyl content of 38.5%; cellulose acetate propionate having anacetyl content of 1.5 to 7% and an acetyl content of 39 to 42%;cellulose acetate propionate having an acetyl content of 2.5 to 3%, anaverage propionyl content of 39.2 to 45%, and a hydroxyl content of 2.8to 5.4%; cellulose acetate butyrate having a DS of 1.8, an acetylcontent of 13 to 15%, and a butyryl content of 34 to 39%; celluloseacetate butyrate having an acetyl content of 2 to 29%, a butyryl contentof 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; cellulosetriacylates having a DS of 2.6 to 3, such as cellulose trivalerate,cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate andcellulose tripropionate; cellulose diesters having a DS of 2.2 to 2.6,such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dicaprylate, and the like; and mixed celluloseesters, such as cellulose acetate valerate, cellulose acetate succinate,cellulose propionate succinate, cellulose acetate octanoate, cellulosevalerate palmitate, cellulose acetate heptanoate, and the like.Semipermeable polymers are known in U.S. Pat. No. 4,077,407, and theycan be synthesized by procedures described in Encyclopedia of PolymerScience and Technology, Vol. 3, pp. 325-354 (1964), IntersciencePublishers Inc., New York, N.Y.

Additional semipermeable polymers for forming the outer wall 2 comprisecellulose acetaldehyde dimethyl acetate; cellulose acetateethylcarbamate; cellulose acetate methyl carbamate; cellulosedimethylaminoacetate; semipermeable polyamide; semipermeablepolyurethanes; semipermeable sulfonated polystyrenes; cross-linkedselectively semipermeable polymers formed by the coprecipitation of ananion and a cation, as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;3,541,005; 3,541,006 and 3,546,142; semipermeable polymers, as disclosedby Loeb, et al. in U.S. Pat. No. 3,133,132; semipermeable polystyrenederivatives; semipermeable poly(sodium styrenesulfonate); semipermeablepoly(vinylbenzyltrimethylammonium chloride); and semipermeable polymersexhibiting a fluid permeability of 10⁻⁵ to 10⁻² (cc. mill/cm hr.atm),expressed as per atmosphere of hydrostatic or osmotic pressuredifferences across a semipermeable wall. The polymers are known to theart in U.S. Pat. Nos. 3,845,770; 3,916,899 and 4,160,020; and inHandbook of Common Polymers, Scott and Roff (1971) CRC Press, Cleveland,Ohio.

Wall 2 also can comprise a flux regulating agent. The flux regulatingagent is a compound added to assist in regulating the fluid permeabilityor flux through wall 2. The flux regulating agent can be a fluxenhancing agent or a decreasing agent. The agent can be preselected toincrease or decrease the liquid flux. Agents that produce a markedincrease in permeability to fluid such as water, are often essentiallyhydrophilic, while those that produce a marked decrease to fluids suchas water, are essentially hydrophobic. The amount of regulator in thewall when incorporated therein generally is from about 0.01% to 20% byweight or more. The flux regulator agents in one embodiment thatincrease flux include polyhydric alcohols, polyalkylene glycols,polyalkylenediols, polyesters of alkylene glycols, and the like. Typicalflux enhancers include polyethylene glycol 300, 400, 600, 1500, 4000,6000 and the like; low molecular weight gylcols such as polypropyleneglycol, polybutylene glycol and polyamylene glycol: thepolyalkylenediols such as poly(1,3-propanediol), poly(1,4-butanediol),poly(1,6-hexanediol), and the like; aliphatic diols such as 1,3-butyleneglycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol, and thelike; alkylene triols such as glycerine, 1,2,3-butanetriol,1,2,4-hexanetriol, 1,3,6-hexanetriol and the like; esters such asethylene glycol dipropionate, ethylene glycol butyrate, butylene glycoldipropionate, glycerol acetate esters and the like. Representative fluxdecreasing agents include phthalates substituted with an alkyl or alkoxyor with both an alkyl and alkoxy group such as diethyl phthalate,dimethoxyethyl phthalate, dimethyl phthalate, and di(2-ethylhexyl)phthalate, aryl phthalates such as triphenyl phthalate, and butyl benzylphthalate; insoluble salts such as calcium sulphate, barium sulphate,calcium phosphate, and the like; insoluble oxides such as titaniumoxide; polymers in powder, granule and like form such as polystyrene,polymethylmethacrylate, polycarbonate, and polysulfone; esters such ascitric acid esters esterified with long chain alkyl groups; inert andsubstantially water impermeable fillers; resins compatible withcellulose based wall forming materials, and the like.

Other materials that can be used to form the wall 2 for impartingflexibility and elongation properties to the wall, for making wall 2less-to-nonbrittle and to render tear strength, include phthalateplasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octylphthalate, straight chain phthalates of six to eleven a carbons,di-isononyl phthalate, di-isodecyl phthalate, and the like. Theplasticizers include nonphthalates such as triacetin, dioctyl azelate,epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl trimellitate,sucrose acetate isobutyrate, epoxidized soybean oil, and the like. Theamount of plasticizer in a wall when incorporated therein is about 0.01%to 20% weight, or higher.

The drug layer 6 comprises a composition formed of an active agent and acarrier, such as a hydrophilic polymer. The hydrophilic polymer providesa hydrophilic polymer particle in the drug composition that contributesto the uniform release rate of active agent and controlled deliverypattern. Representative examples of these polymers are poly(alkyleneoxide) of 100,000 to 750,000 number-average molecular weight, includingpoly(ethylene oxide), poly(methylene oxide), poly(butylene oxide) andpoly(hexylene oxide); and a poly(carboxymethylcellulose) of 40,000 to400,000 number-average molecular weight, represented by poly(alkalicarboxymethylcellulose), poly(sodium carboxymethylcellulose),poly(potassium carboxymethylcellulose) and poly(lithiumcarboxymethylcellulose). The drug composition can comprise ahydroxypropylalkylcellulose of 9,200 to 125,000 number-average molecularweight for enhancing the delivery properties of the dosage form asrepresented by hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose andhydroxypropylpentylcellulose; and a poly(vinylpyrrolidone) of 7,000 to75,000 number-average molecular weight for enhancing the flow propertiesof the dosage form. Preferred among those polymers are the poly(ethyleneoxide) of 100,000-300,000 number average molecular weight. Carriers thaterode in the gastric environment, i.e., bioerodible carriers, areespecially preferred.

Surfactants and disintegrants may be utilized in the carrier as well.Exemplary of the surfactants are those having an HLB value of betweenabout 10-25, such as polyethylene glycol 400 monostearate,polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitanmonooleate, polyoxyethylene-20-sorbitan monopalmitate,polyoxyethylene-20-monolaurate, polyoxyethylene-40-stearate, sodiumoleate and the like. Disintegrants may be selected from starches, clays,celluloses, algins and gums and crosslinked starches, celluloses andpolymers. Representative disintegrants include corn starch, potatostarch, croscarmelose, crospovidone, sodium starch glycolate, Veegum HV,methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid,guar gum and the like.

The drug layer 6 is formed as a mixture containing an active agent andthe carrier. The drug layer may be formed from particles by comminutionthat produces the size of the drug and the size of the accompanyingpolymer used in the fabrication of the drug layer, typically as a corecontaining the compound, according to the mode and the manner of theinvention. The means for producing particles include granulation, spraydrying, sieving, lyophilization, crushing, grinding, jet milling,micronizing and chopping to produce the intended micron particle size.The process can be performed by size reduction equipment, such as amicropulverizer mill, a fluid energy grinding mill, a grinding mill, aroller mill, a hammer mill, an attrition mill, a chaser mill, a ballmill, a vibrating ball mill, an impact pulverizer mill, a centrifugalpulverizer, a coarse crusher and a fine crusher. The size of theparticle can be ascertained by screening, including a grizzly screen, aflat screen, a vibrating screen, a revolving screen, a shaking screen,an oscillating screen and a reciprocating screen. The processes andequipment for preparing drug and carrier particles are disclosed inPharmaceutical Sciences, Remington, 17th Ed., pp. 1585-1594 (1985);Chemical Engineers Handbook, Perry, 6th Ed., pp. 21-13 to 21-19 (1984);Journal of Pharmaceutical Sciences, Parrot, Vol. 61, No. 6, pp. 813-829(1974); and Chemical Engineer, Hixon, pp. 94-103 (1990).

The active compound may be provided in the drug layer in amounts of from1 microgram to 5000 mg per dosage form, depending upon the requireddosing level that must be maintained over the delivery period, i.e., thetime between consecutive administrations of the dosage forms. Moretypically, loading of compound in the dosage forms will provide doses ofcompound to the subject ranging from 1 microgram to 2500 mg per day,more usually 1 mg to 2500 mg per day. In many cases it may be preferableto limit the amount of drug in each dosage form to less than 1000 mg andmeet daily dosing requirements greater than that amount by administeringmore than one dosage form to a subject to meet the daily requirement.The drug layer typically will be a dry composition formed by compressionof the carrier and the drug as one layer and the expandable or pushlayer as the second layer. The expandable layer will push the drug layerfrom the exit orifice as the push layer imbibes fluid from theenvironment of use, and the exposed drug layer will be eroded to releasethe drug into the environment of use. This may be seen with reference toFIG. 1B.

The push layer 5 is an expandable layer having a push-displacementcomposition in direct or indirect contacting layered arrangement withthe drug layer 6. When in indirect contacting layered arrangement, aninert element (not shown), such as a spacer layer or disk, may be placedbetween the drug layer and the push layer.

Push layer 5 comprises a polymer that imbibes an aqueous or biologicalfluid and swells to push the drug composition through the exit means ofthe device. Representatives of fluid-imbibing displacement polymerscomprise members selected from poly(alkylene oxide) of 1 million to 15million number-average molecular weight, as represented by poly(ethyleneoxide) and poly(alkali carboxymethylcellulose) of 500,000 to 3,500,000number-average molecular weight, wherein the alkali is sodium, potassiumor lithium. Examples of additional polymers for the formulation of thepush-displacement composition comprise osmopolymers comprising polymersthat form hydrogels, such as Carbopol® acidic carboxypolymer, a polymerof acrylic cross-linked with a polyallyl sucrose, also known ascarboxypolymethylene, and carboxyvinyl polymer having a molecular weightof 250,000 to 4,000,000; Cyanamer® polyacrylamides; cross-linked waterswellable indenemaleic anhydride polymers; Good-rite® polyacrylic acidhaving a molecular weight of 80,000 to 200,000; Aqua-Keeps® acrylatepolymer polysaccharides composed of condensed glucose units, such asdiester cross-linked polygluran; and the like. Representative polymersthat form hydrogels are known to the prior art in U.S. Pat. No.3,865,108, issued to Hartop; U.S. Pat. No. 4,002,173, issued to Manning;U.S. Pat. No. 4,207,893, issued to Michaels; and in Handbook of CommonPolymers, Scott and Roff, Chemical Rubber Co., Cleveland, Ohio.

The osmagent, also known as osmotic solute and osmotically effectiveagent, which exhibits an osmotic pressure gradient across the outer walland subcoat, comprises a member selected from the group consisting ofsodium chloride, potassium chloride, lithium chloride, magnesiumsulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithiumsulfate, potassium acid phosphate, mannitol, urea, inositol, magnesiumsuccinate, tartaric acid raffinose, sucrose, glucose, lactose, sorbitol,inorganic salts, organic salts and carbohydrates.

Exemplary solvents suitable for manufacturing the respective walls,layers, coatings and subcoatings utilized in the dosage forms of theinvention comprise aqueous and inert organic solvents that do notadversely harm the materials utilized to fabricate the dosage forms. Thesolvents broadly include members selected from the group consisting ofaqueous solvents, alcohols, ketones, esters, ethers, aliphatichydrocarbons, halogenated solvents, cycloaliphatics, aromatics,heterocyclic solvents and mixtures thereof. Typical solvents includeacetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butylalcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane,n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethylacetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon tetrachloride nitroethane, nitropropanetetrachloroethane, ethyl ether, isopropyl ether, cyclohexane,cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran,diglyme, water, aqueous solvents containing inorganic salts such assodium chloride, calcium chloride, and the like, and mixtures thereofsuch as acetone and water, acetone and methanol, acetone and ethylalcohol, methylene dichloride and methanol, and ethylene dichloride andmethanol.

Pan coating may be conveniently used to provide the completed dosageform, except for the exit orifice. In the pan coating system, thesubcoat of the wall-forming compositions is deposited by successivespraying of the respective composition on the bilayered core comprisingthe drug layer and the push layer accompanied by tumbling in a rotatingpan. A pan coater is used because of its availability at commercialscale. Other techniques can be used for coating the drug core. Thecoated dosage form may be dried in a forced-air oven, or in atemperature and humidity controlled oven to free the dosage form ofsolvent. Drying conditions will be conventionally chosen on the basis ofavailable equipment, ambient conditions, solvents, coatings, coatingthickness, and the like.

Other coating techniques can also be employed. For example, thesemipermeable wall and the subcoat of the dosage form can be formed inone technique using the air-suspension procedure. This procedureconsists of suspending and tumbling the bilayer core in a current ofair, an inner subcoat composition and an outer semipermeable wallforming composition, until, in either operation, the subcoat and theouter wall coat is applied to the bilayer core. The air-suspensionprocedure is well suited for independently forming the wall of thedosage form. The air-suspension procedure is described in U.S. Pat. No.2,799,241; in J. Am. Pharm. Assoc., Vol. 48, pp. 451-459 (1959); and,ibid., Vol. 49, pp. 82-84 (1960). The dosage form also can be coatedwith a Wurster® air-suspension coater using, for example, methylenedichloride methanol as a cosolvent. An Aeromatic® air-suspension coatercan be used employing a cosolvent.

The dosage form of the invention may be manufactured by standardtechniques. For example, the dosage form may be manufactured by the wetgranulation technique. In the wet granulation technique, the drug andthe ingredients comprising the first layer or drug composition areblended using an organic solvent, such as denatured anhydrous ethanol,as the granulation fluid. The ingredients forming the first layer ordrug composition are individually passed through a preselected screenand then thoroughly blended in a mixer. Next, other ingredientscomprising the first layer can be dissolved in a portion of thegranulation fluid, such as the solvent described above. Then, the latterprepared wet blend is slowly added to the drug blend with continualmixing in the blender. The granulating fluid is added until a wet blendis produced, which wet mass blend is then forced through a predeterminedscreen onto oven trays. The blend is dried for 18 to 24 hours at 24° C.to 35° C. in a forced-air oven. The dried granules are then sized. Next,magnesium stearate is added to the drug granulation, then put intomilling jars and mixed on a jar mill for 10 minutes. The composition ispressed into a layer, for example, in a Manesty® press. The speed of thepress is set at 20 rpm and the maximum load set at 2 tons. The firstlayer is pressed against the composition forming the second layer andthe bilayer tablets are fed to the Kilian® Dry Coater press andsurrounded with the drug-free coat, followed by the exterior wallsolvent coating.

In another manufacture the beneficial drug and other ingredientscomprising the first layer facing the exit means are blended and pressedinto a solid layer. The layer possesses dimensions that correspond tothe internal dimensions of the area the layer is to occupy in the dosageform, and it also possesses dimensions corresponding to the second layerfor forming a contacting arrangement therewith. The drug and otheringredients can also be blended with a solvent and mixed into a solid orsemisolid form by conventional methods, such as ballmilling,calendering, stirring or rollmilling, and then pressed into apreselected shape. Next, the expandable layer, e.g., a layer ofosmopolymer composition, is placed in contact with the layer of drug ina like manner. The layering of the drug formulation and the osmopolymerlayer can be fabricated by conventional two-layer press techniques. Thetwo contacted layers are first coated with the flow-promoting subcoatand then an outer semipermeable wall. The air-suspension andair-tumbling procedures comprise in suspending and tumbling the pressed,contacting first and second layers in a current of air containing thedelayed-forming composition until the first and second layers aresurrounded by the wall composition.

Another manufacturing process that can be used for providing thecompartment-forming composition comprises blending the powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for example,poly(vinylpyrrolidone) in water, is sprayed onto the powders. The coatedpowders are then dried in the granulator. This process granulates allthe ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant, such as stearic acid ormagnesium stearate, is mixed into the granulation using a tote orV-blender. The granules are then pressed in the manner described above.

The dosage form of the invention is provided with at least one exitorifice. The exit orifice cooperates with the drug core for the uniformrelease of drug from the dosage form. The exit orifice can be providedduring the manufacture of the dosage form or during drug delivery by thedosage form in a fluid environment of use. The expression “exit orifice”as used for the purpose of this invention includes a member selectedfrom the group consisting of a passageway; an aperture; an orifice; anda bore. The expression also includes an orifice that is formed from asubstance or polymer that erodes, dissolves or is leached from the outercoat or wall or inner coat to form an exit orifice. The substance orpolymer may include an erodible poly(glycolic) acid or poly(lactic) acidin the outer or inner coats; a gelatinous filament; a water-removablepoly(vinyl alcohol); a leachable compound, such as a fluid removablepore-former selected from the group consisting of inorganic and organicsalt, oxide and carbohydrate. An exit, or a plurality of exits, can beformed by leaching a member selected from the group consisting ofsorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodiumchloride, potassium chloride, sodium citrate and mannitol to provide auniform-release dimensioned pore-exit orifice. The exit orifice can haveany shape, such as round, triangular, square, elliptical and the likefor the uniform metered dose release of a drug from the dosage form. Thedosage form can be constructed with one or more exits in spaced apartrelation or one or more surfaces of the dosage form. The exit orificecan be performed by drilling, including mechanical and laser drilling,through the outer coat, the inner coat, or both. Exits and equipment forforming exits are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899,by Theeuwes and Higuchi; in U.S. Pat. No. 4,063,064, by Saunders, etal.; and in U.S. Pat. No. 4,088,864, by Theeuwes, et al. The exitorifice may be from 10% to 100% of the inner diameter of the compartmentformed by wall 2, preferably from 30% to 100%, and most preferably from50% to 100%.

Notwithstanding that some of the dosage forms of the invention mayrequire high drug loading to elicit a desired patient response, dosageforms of the present invention which provide a uniform release rate ofthe active compound may allow one to use a lesser amount of compound perdosage form per day than would be calculated from simply multiplying thedose of active agent in the immediate release product by the number oftimes it is recommended to administer the immediate release product in aday.

Even at high dosage levels in which the active compound is present from40% to 90% by weight of the drug layer composition, the instant dosageforms and devices are able to effectively release the required amount ofactive compound over a prolonged period of time at a uniform releaserate. Preferably, the weight percent of active compound in the dosageforms of the invention will be 75% or less, and most preferably lessthan 70%, but 40% or greater, most preferably greater than 60%, based onthe weight of drug layer composition, to allow for dosage forms that maybe easily swallowed. In circumstances where it is desirable toadminister an amount of drug that would exceed 75% of the drug layercomposition, it is usually preferred to simultaneously administer twotablets or more of the dosage form with a total drug loading equal tothe greater amount that would have been used in the single tablet.

The invention may be illustrated with once-a-day dosage forms preparedwith 100 mg, 200 mg, 300 mg, 400 mg and 500 mg of nefazodonehydrochloride per dosage form. In each case, less than 10% of theinitial quantity of drug remained in the dosage form after 24 hours whentested in the release rate assay. After an initial start-up period,usually approximately 2-3 hours or less, the dosage forms provide auniform rate of release of compound over a prolonged period of time,typically 4 hours to 20 hours or more, often for 4 hours to 16 hours,and more usually for a time period of 4 hours to 10 hours. At the end ofa prolonged period of uniform release, the rate of release of drug fromthe dosage form may decline somewhat over a period of time, such asseveral hours. The dosage forms provide therapeutically effectiveamounts of drug for a broad range of applications and individual subjectneeds.

Upon initial administration, the dosage forms may provide a drugconcentration in the plasma of the subject that increases over aninitial period of time, typically several hours or less, and thenprovide a relatively constant concentration of drug in the plasma over aprolonged period of time, typically 4 hours to 24 hours or more. Therelease profiles of the dosage forms of this invention provide releaseof drug over the entire 24-hour period corresponding to once-a-dayadministration, such that steady state concentration of drug in bloodplasma of a subject may be maintained at therapeutically effectivelevels over a 24 hour period after administration the sustained releasedosage form. Steady state plasma levels of drug may typically beachieved after twenty-four hours or, in some cases, several days, e.g.,2-5 days, in most subjects.

For systems having 100 mg, 200 mg, 300 mg, 400 mg and 500 mg ofnefazodone hydrochloride, manufactured substantially in accordance withthe procedures described in Example 1 and having a T₉₀ of 12 hours, forexample, nefazodone hydrochloride is released at average release ratesof 8.6, 17.2, 25.8, 34.4 and 43.0 mg per hour, respectively, over acontinuous period of time of 4 hours or more, generally for a continuousperiod of about 4 to 10 hours, as determined in the release rate assay,beginning approximately 2-3 hours after initial exposure to the bath. Ineach of those formulations, the percentage of drug loading based on theoverall weight of the drug layer is about 69% for the 100 mg, 200 mg,300 mg, 400 mg and 500 mg dosage forms. In each instance nefazodonehydrochloride was released from the dosage form at a uniform releaserate over a prolonged period of time.

Release rate as a function of time for a representative dosage formcontaining 400 mg of nefazodone hydrochloride is illustrated in FIG. 2.The dosage form had a T₉₀ equal to 17.7 hours and a mean release rate ofabout 22 mg/hr. The dosage form was fabricated with an exit orifice of190 mils, a 40 mg subcoat formed of 70/30 wt % Klucel/PVPK29-32 and asemipermeable membrane coat weighing 70.4 mg of 90/10 wt % celluloseacetate 398 and polyethylene glycol 3350. In FIG. 3 the release ratesfor a similarly fabricated dosage form having a T₉₀ of 18.5 hours and amean release rate of about 5.2 mg/hr is illustrated. The dosage form isfabricated with an exit orifice of 117 mils, a 10.6 mg subcoat formed of70/30 wt % Klucel/PVPK29-32 and a semipermeable membrane coat weighing46.9 mg of 97/3 wt % cellulose acetate 398 and polyethylene glycol 3350.In each case, the drug layer contained 65% nefazodone hydrochloride. Ascan be seen from those figures, the prolonged period of uniform rate ofrelease extends from approximately 4 hours to about 18 hours for thedosage form of FIG. 2 and from about 2 hours to about 16 hours for thedosage form of FIG. 3.

With respect to the 100-400 mg dosage forms prepared as describedherein, it has been found that, for a 100 mg dosage form having a corediameter of about {fraction (3/16)} inch, an exit orifice of 110-130mils, preferably 115-125 mils, and most preferably 120 mils, provides aneffective release profile. For a 200 mg dosage form having a corediameter of about {fraction (15/64)} inch, an exit orifice of 145-165mils, preferably 150-160 mils, and most preferably 155 mils, provides aneffective release profile. For a 300 mg dosage form having a corediameter of about {fraction (17/64)} inch, an exit orifice of 165-185mils, preferably 170-180 mils, and most preferably 175 mils, provides aneffective release profile. For a 400 mg dosage form having a corediameter of about {fraction (9/32)} inch, an exit orifice of 180-200mils, preferably 185-195 mils, and most preferably 190 mils, provides aneffective release profile. The dosage forms release drug at a rate thatvaries less than 30% from the mean rate of release measured over aprolonged period of time. Preferably, the devices release drug at a ratethat varies less than 25% from the mean rate of release measured over aprolonged period of time.

Dosage forms of this invention release drug at a uniform rate of releaseover a prolonged period of time as determined in a standard release rateassay such as that described herein. When administered to a subject, thedosage forms of the invention provide blood plasma levels of drug in thesubject that are less variable over a prolonged period of time thanthose obtained with immediate release dosage forms. When the dosageforms of this invention are administered on a regular, once-a-day basis,the dosage forms of the invention provide steady state plasma levels ofdrug such that the difference between C_(max) and C_(min) over the24-hour period is substantially reduced over that obtained fromadministration of an immediate release product that is intended torelease the same amount of drug in the 24-hour period as is providedfrom the dosage forms of the invention

The dosage forms of this invention are adapted to release active agentat a uniform rate of release rate over a prolonged period of time,preferably 6 hours or more. Measurements of release rate are typicallymade in vitro, in acidified water to provide a simulation of conditionsin gastric fluid, and are made over finite, incremental time periods toprovide an approximation of instantaneous release rate. Information ofsuch in vitro release rates with respect to a particular dosage form maybe used to assist in selection of dosage form that will provide desiredin vivo results. Such results may be determined by present methods, suchas blood plasma assays and clinical observation, utilized bypractitioners for prescribing available immediate release dosage forms.

It has been found that dosage forms of the present invention havingrelease rate profiles as defined herein may provide to a patient asubstantially constant blood plasma concentration and a sustainedtherapeutic effect of active agent, after administration of the dosageform, over a prolonged period of time. The sustained release dosageforms of this invention demonstrate less variability in drug plasmaconcentration over a 24-hour period than do immediate releaseformulations, which characteristically create significant peaks in drugconcentration shortly or soon after administration to the subject.

The practice of the foregoing method by orally administering a dosageform of the invention to a subject once-a-day for the treatment ofdisease states or symptoms responsive to the active agent of the dosageform is preferred.

A preferred method of manufacturing dosage forms in accordance with thepresent invention is generally described below. Percentages arepercentages by weight unless noted otherwise.

EXAMPLE 1

Preparation of the Drug Layer Granulation

A binder solution is prepared by adding hydroxypropyl cellulose (KlucelMF, Aqualon Company), “HPC”, to water to form a solution containing 5 mgof HPC per 0.995 grams of water. The solution is mixed until thehydroxypropyl cellulose is dissolved. For a particular batch size, afluid bed granulator (“FBG”) bowl is charged with the required amountsof nefazodone HCI (69.0%), polyethylene oxide (MW 200,000) (Polyox®N-80, Union Carbide Corporation) (20.3%), hydroxypropyl cellulose(Klucel MF) (5%), polyoxyl 40 stearate (3%) and crospovidone (2%). Aftermixing the dry materials in the bowl, the binder solution prepared asabove is added. Then the granulation is dried in the FBG to aconsistency suitable for milling (<1% by weight water), and thegranulation is milled through a 7 or a 10 mesh screen.

The granulation is transferred to a tote blender or a V-blender. Therequired amounts of antioxidant, butylated hydroxytoluene (“BHT”)(0.01%), and lubricant, stearic acid (1%), are sized through a 40 meshscreen and both are blended into the granulation using the tote orV-blender until uniformly dispersed (about 1 minute of blending forstearic acid and about 10 minutes of blending for BHT.

Preparation of the Osmotic Push Layer Granulation

A binder solution is prepared by adding hydroxypropyl methylcellulose2910 (“HPMC”) to water in a ratio of 5 mg of HPMC to 1 g of water. Thesolution is mixed until the HPMC is dissolved. Sodium chloride powder(30%) and red ferric oxide (1.0%) are milled and screened. A fluid bedgranulator (“FBG”) bowl is charged with the required amounts ofpolyethylene oxide (MW 7,000,000) (Polyox® 303) (63.7%), HPMC (5.0%),the sodium chloride and the red ferric oxide. After mixing the drymaterials in the bowl, the binder solution prepared above is added. Thegranulation is dried in the FBG until the target moisture content (<1%by weight water) is reached. The granulation is milled through a 7 meshscreen and transferred to a tote blender or a V-blender. The requiredamount of antioxidant, butylated hydroxytoluene (0.08%), is sizedthrough a 60 mesh screen. The required amount of lubricant, stearic acid(0.25%), is sized through a 40 mesh screen and both materials areblended into the granulation using the tote or V-blender until uniformlydispersed (about 1 minute for stearic acid and about 10 minutes forBHT).

Bilayer Core Compression

A longitudinal tablet press (Korsch press) is set up with round, deepconcave punches and dies. Two feed hoppers are placed on the press. Thedrug layer prepared as above is placed in one of the hoppers while theosmotic push layer prepared as above is placed in the remaining hopper.

The initial adjustment of the tableting parameters (drug layer) isperformed to produce cores with a uniform target drug layer weight,typically 100 mg of drug in each tablet. The second layer adjustment(osmotic push layer) of the tableting parameters is performed whichbonds the drug layer to the osmotic layer to produce cores with auniform final core weight, thickness, hardness, and friability. Theforegoing parameters can be adjusted by varying the fill space and/orthe force setting. A typical tablet containing a target amount of 100 mgof drug will be approximately 0.465 inches long and approximately 0.188inches in diameter.

Preparation of the Subcoat Solution and Subcoated System

The subcoat solution is prepared in a covered stainless steel vessel.The appropriate amounts of povidone (K29-32) (2.4%) and hydroxypropylcellulose (MW 80,000) (Klucel EF, Aqualon Company) (5.6%) are mixed intoanhydrous ethyl alcohol (92%) until the resulting solution is clear. Thebilayer cores prepared above are placed into a rotating, perforated pancoating unit. The coater is started and after the coating temperature of28-36° C. is attained, the subcoating solution prepared above isuniformly applied to the rotating tablet bed. When a sufficient amountof solution has been applied to provide the desired subcoat weight gain,the subcoat process is stopped. The desired subcoat weight will beselected to provide acceptable residuals of drug remaining in the dosageform as determined in the release rate assay for a 24-hour period.Generally, it is desirable to have less than 10%, more preferably lessthan 5%, and most preferably less than 3% of residual drug remainingafter 24 hours of testing in a standard release rate assay as describedherein, based on the initial drug loading. This may be determined fromthe correlation between subcoat weight and the residual drug for anumber of dosage forms having the same bilayer core but differentsubcoat weights in the standard release rate assay.

Preparation of the Rate Controlling Membrane and Membrane Coated System

Subcoated bilayer cores prepared as above are placed into a rotating,perforated pan coating unit. The coater is started, and after thecoating temperature (28-38° C.) is attained, the appropriate coatingsolution prepared as in A, B or C below is uniformly applied to therotating tablet bed until the desired membrane wt gain is obtained. Atregular intervals throughout the coating process, the weight gain isdetermined and sample membrane coated units may be tested in the releaserate assay to determine a T₉₀ for the coated units. Weight gain may becorrelated with T₉₀ for membranes of varying thickness in the releaserate assay. When sufficient amount of solution has been applied,conveniently determined by attainment of the desired membrane weightgain for a desired T₉₀, the membrane coating process is stopped.

A. A coating solution is prepared in a covered stainless steel vessel.The appropriate amounts of acetone (565 mg) and water (29.7 mg) aremixed with the poloxamer 188 (1.6 mg) and cellulose acetate (29.7 mg)until the solids are completely dissolved. The coating solution hasabout 5% solids upon application. The membrane yields a dosage formhaving a T₉₀ of about 13 hours in the release rate assay.

B. Acetone (505.4 mg) is mixed with cellulose acetate (27.72 mg) untilthe cellulose acetate is completely dissolved. Polyethylene glycol 3350(0.28 mg) and water (26.6 mg) are mixed in separate container. The twosolutions are mixed together until the resulting solution is clear. Thecoating solution has about 5% solids upon application. The membraneyields a dosage form having a T₉₀ of about 13 hours (i.e., approximately90% of the drug is released from the dosage form in 13 hours), asdetermined in the release rate assay.

C. Acetone (776.2 mg) is mixed with cellulose acetate (42.57 mg) untilthe cellulose acetate is completely dissolved. Polyethylene glycol 3350(0.43 mg) and water (40.9 mg) are mixed in separate container. The twosolutions are mixed together until the resulting solution is clear. Thecoating solution has about 5% solids upon application. The membraneyields a dosage form having a T₉₀ of about 18 hours (i.e., approximately90% of the drug is released from the dosage form in 18 hours), asdetermined in the release rate assay.

Drilling of Membrane Coated Systems

One exit port is drilled into the drug layer end of the membrane coatedsystem. During the drilling process, samples are checked at regularintervals for orifice size, location, and number of exit ports.

Drying of Drilled Coated Systems

Drilled coated systems prepared as above are placed on perforated oventrays which are placed on a rack in a relative humidity oven (43-45%relative humidity) and dried to remove the remaining solvents.

Color and Clear Overcoats

Optional color or clear coats solutions are prepared in a coveredstainless steel vessel. For the color coat 88 parts of purified water ismixed with 12 parts of Opadry II [color not critical] until the solutionis homogeneous. For the clear coat 90 parts of purified water is mixedwith 10 parts of Opadry Clear until the solution is homogeneous. Thedried cores prepared as above are placed into a rotating, perforated pancoating unit. The coater is started and after the coating temperature isattained (35-45° C.), the color coat solution is uniformly applied tothe rotating tablet bed. When sufficient amount of solution has beenapplied, as conveniently determined when the desired color overcoatweight gain has been achieved, the color coat process is stopped. Next,the clear coat solution is uniformly applied to the rotating tablet bed.When sufficient amount of solution has been applied, or the desiredclear coat weight gain has been achieved, the clear coat process isstopped. A flow agent (e.g., Car-nu-bo wax) is applied to the tablet bedafter clear coat application.

EXAMPLE 2

The release rate of drug from devices containing the dosage forms of theinvention is determined in the following standardized assay. The methodinvolves releasing systems into acidified water (pH 3). Aliquots ofsample release rate solutions are injected onto a chromatographic systemto quantify the amount of drug released during specified test intervals.Drug is resolved on a C₁₈ column and detected by UV absorption (254 nmfor nefazodone hydrochloride). Quatitation is performed by linearregression analysis of peak areas from a standard curve containing atleast five standard points.

Samples are prepared with the use of a USP Type 7 Interval ReleaseApparatus. Each system (invention device) to be tested is weighed. Then,each system is glued to a plastic rod having a sharpened end, and eachrod is attached to a release rate dipper arm. Each release rate dipperarm is affixed to an up/down reciprocating shaker (USP Type 7 IntervalRelease Apparatus), operating at an amplitude of about 3 cm and 2 to 4seconds per cycle. The rod ends with the attached systems arecontinually immersed in 50 ml calibrated test tubes containing 50 ml ofacidified H₂O (acidified to pH 3.00±0.05 with phosphoric acid),equilibrated in a constant temperature water bath controlled at 37°C.±0.5° C. At the end of each time interval specified, typically onehour or two hours, the systems are transferred to the next row of testtubes containing fresh acidified water. The process is repeated for thedesired number of intervals until release is complete. Then the solutiontubes containing released drug are removed and allowed to cool to roomtemperature. After cooling, each tube is filled to the 50 ml mark withacidified water, each of the solutions is mixed thoroughly, and thentransferred to sample vials for analysis by high pressure liquidchromatography (“HPLC”). Standard solutions of drug are prepared inconcentration increments encompassing the range of 5 micrograms to about400 micrograms and analyzed by HPLC. A standard concentration curve isconstructed using linear regression analysis. Samples of drug obtainedfrom the release test are analyzed by HPLC and concentration of drug isdetermined by linear regression analysis. The amount of drug released ineach release interval is calculated. The results for various dosageforms of the invention are 16 illustrated in FIGS. 2-13.

EXAMPLE 3

Employing the general procedure of EXAMPLE 1 and proportionate amountsof materials (all percentages expressed as weight percentages), thefollowing dosage form containing 100 mg nefazodone hydrochloride isprepared.

A drug layer having a weight of 145.0 mg consisting of 69% nefazodonehydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5% hydroxypropylcellulose (Klucel MF), 3% polyoxyl 40 stearate (MYRJ 52S), 2%crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight of 92 mg consisting of 63.67% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 1%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

Next, a subcoat is prepared with 70% Klucel EF and 30% povidone K29-32with ethanol as the solvent. The subcoat contains 8% solids onapplication. After application, the amount of the subcoat on the bilayercore is 13.5 mg. The semi-permeable membrane is prepared with 99%cellulose acetate 398-10 and 1% polyethylene glycol 3350 with a solventsystem of 95% acetone and 5% water. The membrane coat contains 5% solidson application, and the weight of the membrane on the subcoated bilayercore after application is 43.8 mg.

An orifice having a diameter of 114 mils is drilled in the dosage forms,which are then dried at 45° C. and 45% relative humidity for about 120hours and dried for an additional 5 hours at 45° C. at otherwise ambientconditions.

The dosage forms are assayed for release of nefazodone hydrochloride inthe assay described in Example 2. The release rates for twelveindividual dosage forms and the cumulative percent of dose released arerepresented in FIG. 5 and FIG. 6, respectively. The dosage forms exhibita nominal T₉₀ of 18.3 hours and a mean release rate of 5.2 mg/hr over aprolonged period of time, extending substantially from interval 4 tointerval 18. It is observed that the dosage forms release nefazodonehydrochloride at a uniform rate of release over a prolonged period oftime.

When the weight of cellulose acetate in the semi-permeable membrane isreduced to 28.5 mg, 1.5 mg of poloxamer 188 is substituted for thepolyethylene glycol plasticizer, and the semi-permeable membrane isapplied to achieve a per dosage weight of about 26 mg, a dosage formhaving a T₉₀ of about 12 hours is produced.

When the weight of cellulose acetate in the semi-permeable membrane isreduced to 27.2 mg and the amount of polyethylene glycol plasticizer isreduced to 0.28 mg, and the semi-permeable membrane is applied toachieve a per dosage weight of about 28 mg, a dosage form having a T₉₀of about 13 hours is produced.

EXAMPLE 4

Employing the general procedure of EXAMPLE 1 and proportionate amountsof materials (all percentages expressed as weight percentages), thefollowing dosage form containing 200 mg nefazodone hydrochloride isprepared:

A drug layer having a weight of 290 mg consisting of 69% nefazodonehydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5% hydroxypropylcellulose (Klucel MF), 3% polyoxyl 40 stearate (MYRJ 52S), 2%crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight 145 mg consisting of 64.10% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 0.5%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

Next, a subcoat is prepared with 70% Klucel EF and 30% povidone K29-32with ethanol as the solvent. After application, the amount of thesubcoat on the bilayer core is 23.6 mg. The semi-permeable membrane isprepared with 90% cellulose acetate 398-10 and 10% polyoxamer (PluronicsF68, BASF Corporation) with a solvent system of 95% acetone and 5%water. The weight of the membrane coat on the subcoated bilayer coreafter application is 37.5 mg.

An orifice having a diameter of 155 mils is drilled in the dosage forms,which are then dried at 45° C. and 45% relative humidity for about 120hours and dried for an additional 5 hours at 45° C. at otherwise ambientconditions.

The dosage forms are assayed for release of nefazodone hydrochloride inthe assay described in Example 2. The release rates for five individualdosage forms and the cumulative percent of dose released are representedin FIG. 7 and FIG. 8, respectively. The dosage forms exhibit a nominalT₉₀ of 15.1 hours and a mean release rate of 13.4 mg/hr over a prolongedperiod of time, extending substantially from interval 4 to interval 10.The dosage forms release nefazodone hydrochloride at a uniform releaserate over a prolonged period of time.

EXAMPLE 5

Employing the general procedure of EXAMPLE 1 and proportionate amountsof materials (all percentages expressed as weight percentages), thefollowing dosage form containing 300 mg nefazodone hydrochloride isprepared:

A drug layer having a weight of 435 mg consisting of 69% nefazodonehydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5% hydroxypropylcellulose (KIucel MF), 3% polyoxyl 40 stearate (MYRJ 52S), 2%crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight of 174 mg consisting of 64.1% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 0.5%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

Next, a subcoat is prepared with 70% Klucel EF and 30% povidone K29-32with ethanol as the solvent. After application, the amount of thesubcoat on the bilayer core is 31.4 mg. The semi-permeable membrane isprepared with 85% cellulose acetate 398-10 and 15% poloxamer (PluronicsF68) with a solvent system of 95% acetone and 5% water. The weight ofthe membrane on the subcoated bilayer core after application is 40.3 mg.

An orifice having a diameter of 175 mils is drilled in the dosage forms,which are then dried at 45° C. and 45% relative humidity for about 120hours and dried for an additional 5 hours at 45° C. at otherwise ambientconditions.

The dosage forms are assayed for release of nefazodone hydrochloride inthe assay described in Example 2. The release rates for five individualdosage forms and the cumulative percent of dose released are representedin FIG. 9 and FIG. 10, respectively. The dosage forms exhibit a nominalT₉₀ of 11.9 hours and a mean release rate of 26.7 mg/hr over a prolongedperiod of time, extending substantially from interval 4 to interval 10.The dosage forms release nefazodone hydrochloride at uniform rate ofrelease over a prolonged period of time.

EXAMPLE 6

Employing the general procedure of EXAMPLE 1 and proportionate amountsof materials (all percentages expressed as weight percentages), thefollowing dosage form containing 400 mg nefazodone hydrochloride isprepared:

A drug layer having a weight of 580.0 mg consisting of 69% nefazodonehydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5% hydroxypropylcellulose (Klucel MF), 3% polyoxyl 40 stearate (MYRJ 52S), 2%crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight of 232.0 mg consisting of 64.1% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 0.5%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

Next, a subcoat is prepared with 70% Klucel EF and 30% povidone K29-32with ethanol as the solvent. After application, the amount of thesubcoat on the bilayer core is 36.3 mg. The semi-permeable membrane isprepared with 80% cellulose acetate 398-10 and 20% poloxamer F68 with asolvent system of 95% acetone and 5% water. The weight of the membranecoat on the subcoated bilayer core after application is 88.7 mg

An orifice having a diameter of 190 mils is drilled in the dosage forms,which are then dried at 45° C. and 45% relative humidity for about 120hours and dried for an additional 5 hours at 45° C. at otherwise ambientconditions.

The dosage forms are assayed for release of nefazodone hydrochloride inthe assay described in Example 2. The release rates for five individualdosage forms and the cumulative percent of dose released are representedin FIG. 11 and FIG. 12, respectively. The dosage forms exhibit a nominalT₉₀ of 14 hours and a mean release rate of 29.7 mg/hr over a prolongedperiod of time, extending substantially from interval 5 to interval 13.The dosage forms uniformly release nefazodone hydrochloride over aprolonged period of time.

EXAMPLE 7

Representative samples of the dosage forms of this invention containing100-600 mg of nefazodone hydrochloride having orifice diameters of110-200 mils are orally administered to subjects once-a-day. Bloodsamples are drawn from the subjects at regular intervals (typically 1-4hours) and the blood plasma samples so obtained analyzed for amounts ofnefazodone hydrochloride present. The dosage forms of the inventionprovide sustained blood plasma levels of between 5 ng/ml and 2500 ng/ml.Steady state blood plasma levels are maintained at uniformly therapeuticlevels such that quotient that is formed from [C_(max)—C_(min)]/C_(min)for nefazodone hydrochloride in plasma over the 24-hour interval afteradministration is 3 or less.

Surprisingly, the flow-promoting wall 7 provides for substantiallycomplete release, i.e. 80% or greater by weight, of drug from the dosageforms fabricated in accordance with this invention. In dosage forms inwhich there is high-drug loading, i.e., 40% or greater active agent inthe drug layer based on the overall weight of the drug layer, and in theabsence of flow-promoting layer 7, it has been observed that significantresidual amounts of drug may remain in a device such as described hereinafter the period of delivery has been completed. In some instanceswithout the flow promoting layer, amounts of greater than 20% remainedin the device at the end of a twenty-four hour period. Residual drugamounts were reduced by the addition of an inner coat of ahydroxyalkylcellulose applied to the drug layer. When the inner coatcomprised hydroxypropylcellulose (Klucel EF) having a number averagemolecular weight of 80,000, the subcoat weights to obtain 7%, 4% and 3%residual drug content, were, as a percentage of bilayer core weight, 9%,12% and 15%, respectively. The flow-promoting layer or inner wall 7reduces the frictional forces between the semipermeable wall 2 and theexternal surface of the drug layer, thus allowing for more completedelivery of drug from the device. Particularly in the case of activecompounds having a high cost, such an improvement presents substantialeconomic advantages since it is not necessary to load the drug layerwith an excess to insure that the minimal amount required will bedelivered.

EXAMPLE 8

Employing the general procedure of EXAMPLE 1, dosage forms containing400 mg of nefazodone hydrochloride, comprising 83% of the drug layerweighing 482 mg, and having a 14.1 mg subcoat forming the flow promotinglayer and 81.3 mg of the semipermeable membrane are prepared with anexit orifice of 155 mils in the end of the dosage form. Similarly,dosage forms containing the same amount of nefazodone hydrochloride and83.7 mg of the semipermeable membrane and having an exit orifice of 155mils on the end of the dosage form, but without a subcoat, are prepared.Representative dosage forms were tested in the release rate assay, andthe results are shown graphically in FIGS. 13A-13D. Results for thesubcoated dosage forms are shown in FIG. 13A, illustrating an averagerelease rate of about 10.3 mg/hour that is substantially zero order, andFIG. 13B, illustrating the cumulative release rate having a T₉₀ of about26.6 hours. In contrast, the results for the uncoated dosage formpresented in FIGS. 13C and 13D illustrate a varying release rate withonly about 55% of the drug released after 26 hours. The dosage formsfabricated with the flow promoting layer applied as a subcoat providecontrolled release of the drug over a prolonged period of time withminimal residual drug remaining in the dosage form 24 hours afteradministration.

The present invention comprises the following characteristics andfeatures, either alone or in combination with one or more of each other:

-   -   a dosage form for an active agent comprising a wall defining a        cavity, the wall having an exit orifice formed or formable        therein and at least a portion of the wall being semipermeable,        an expandable layer located within the cavity remote from the        exit orifice and in fluid communication with the semipermeable        portion of the wall, a drug layer located within the cavity        adjacent the exit orifice and in direct or indirect contacting        relationship with the expandable layer, and a flow-promoting        layer interposed between the inner surface of the wall and at        least the external surface of the drug layer located within the        cavity; the dosage form wherein the drug layer contains at least        40% by weight of drug based on the weight of the drug layer; the        dosage form wherein the expandable layer comprises an osmotic        agent; the dosage form wherein the flow-promoting layer        comprises a material selected from hydrogels, gelatin,        polyethylene oxides of less than 100,000 MW,        hydroxyalkylcelluloses having number average molecular weights        of between 9,500 and 1,250,000, and hydroxyalkyl alkylcelluloses        having number average molecular weights of between 80,000 to        850,000, and mixtures thereof; the dosage form wherein the        flow-promoting layer is adapted to facilitate release of at        least 80% of the drug in the drug layer to the environment of        use; an article of manufacture comprising a compressed drug        composition overcoated with a flow-promoting layer; the article        of manufacture comprising an expandable layer in direct or        indirect contact with the drug composition and forming a bilayer        core with the drug composition, wherein the bilayer core is        overcoated with the flow-promoting layer; the article of        manufacture wherein the flow-promoting layer comprises a        material selected from hydrogels, gelatin, polyethylene oxides        of less than 100,000 MW, hydroxyalkylcelluloses having number        average molecular weights of between 9,500 and 1,250,000, and        hydroxyalkyl alkylcelluloses having number average molecular        weights of between 80,000 to 850,000, and mixtures thereof; and        a method of facilitating the release of a drug from a dosage        form comprising a compressed drug composition, a semipermeable        wall and a push-layer, the method comprising interposing a        flow-promoting layer between the semi-permeable wall and the        compressed drug composition.

The above-described exemplary embodiments are intended to beillustrative in all respects, rather than restrictive, of the presentinvention. Thus, the present invention is capable of implementation inmany variations and modifications that can be derived from thedescription herein by a person skilled in the art. All such variationsand modifications are considered to be within the scope and spirit ofthe present invention as defined by the following claims.

1. A dosage form for an active agent comprising: A wall defining acavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity; a dry or substantially dry state drug layerlocated within the cavity adjacent the exit orifice and in contactingrelationship with the expandable layer; and a flow-promoting layerinterposed at least partially between the wall and the drug layer. 2.The dosage form of claim 1 wherein the drug layer contains at least 40%by weight of drug based on the weight of the drug layer.
 3. The dosageform of claim 1 wherein the expandable layer comprises an osmotic agent.4. The dosage form of claim 3 wherein the flow-promoting layer comprisesa material selected from hydrogels, gelatin, polyethylene oxides of lessthan 100,000 MW, hydroxyalkylcelluloses having number average molecularweights of between 9,500 and 1,250,000, and hydroxyalkyl alkylcelluloseshaving number average molecular weights of between 80,000 to 850,000,and mixtures thereof.
 5. The dosage form of claim 1 wherein theflow-promoting layer is adapted to facilitate release of at least 80% ofthe drug in the drug layer to the environment of use.
 6. A method offacilitating the release of a drug from a dosage form comprising a dryor substantially dry state compressed drug composition, a semipermeablewall and a push layer, the method comprising interposing aflow-promoting layer at least partially between the semipermeable walland the compressed drug composition.
 7. The method of claim 6 whereinthe flow promoting layer comprises a coating on the compressed drugcomposition prepared from a hydroxyalky cellulose and a lower arkanol.